Homeostasis of blood vessels is maintained by various functions of endothelial cells. The vascular endothelial cells have 1) an effect of mediating transportation of necessary components such as nutrition in blood to tissues and preventing unnecessarily much components from passing, 2) an effect of circulating blood smoothly without coagulation, 3) an effect of stopping hemorrhage when the blood vessels are transected, and 4) a regulatory effect of keeping vasotonia constant.
Angiogenesis occurs stepwise as follows; decomposition of a basement membrane by protease produced by the vascular endothelial cells, migration and proliferation of the vascular endothelial cells, tube formation of the vascular endothelial cells, formation of the basement membrane and encirclement of peripheral cells. The angiogenesis is closely related to various diseases, particularly diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis, corneal neovasculature, solid tumors, hemangioma, proliferation and transfer of tumors and the like. Angiogenesis is caused by various proliferation factors, cytokine, arachidonic acid metabolites, monobutyrin and the like. The proliferation factors are considered to be the most important angiogenesis factors among them (Journal of Clinical and Experimental Medicine, 170, 536-539 (1994)).
Thus, it is meaningful to search compounds having angiogenesis inhibitory actions which are useful as therapeutic agents for diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis, corneal neovasculature, solid tumors, hemangioma, proliferation and transfer of tumors and the like.